It has long been recognized that some type of reserve can protect the nervous system from expressing injury or pathology as functional impairment or clinically diagnosed disease. The overall goal of the proposed study is to identify the structural bases of neural reserve and examine the neurobiologic mechanisms through which environmental and genetic risk factors lead to the functional consequences of aging and Alzheimer's disease. We hypothesize that redundancy of several cellular and subcellular components of the neural systems responsible for cognitive and motor function are crucial for efficient performance of these systems and thereby comprise the structural basis of neural reserve. Furthermore, we hypothesize that some risk factors lead to the clinical expression of disease by promoting the accumulation of disease pathology within selectively vulnerable neural systems, whereas other risk factors reduce the likelihood that disease pathology is expressed clinically by increasing or maintaining reserve capacity (i.e., the ability of the nervous system to tolerate pathology thereby delaying the clinical expression of Alzheimer's disease and other common diseases). To test these hypotheses, we propose a longitudinal, epidemiologic clinical-pathologic study of 1,200 older persons with a wide range of educational and lifetime experiences who agree to annual detailed clinical evaluation and brain donation after death. Identifying factors that increase or maintain neural reserve offers a new and potentially powerful method whereby the clinical signs of Alzheimer's disease and other neurodegenerative conditions can be delayed. Even relatively small reductions of risk from common disabling conditions will have a major public health impact for future generations.